The secretion of parathyroid hormone (PTH) by the parathyroid gland is directly regulated by extracellular calcium ions (Ca2+) via the Ca2+-sensing receptor. However, there are reports of magnesium (Mg2+) effect on PTH secretion: acute hypermagnesemia can suppress PTH and it is suggested that the mechanism of suppression is similar to that of hypercalcemia. During platelet apheresis, the infused citrate forms complexes with both Ca2+ and Mg2+ ions and, therefore, decreases the concentration of the bioactive forms ("ionized" Ca and Mg) of both cations in the blood returned to the donor. The resulting hypocalcemia and concomitant hypomagnesemia could influence the PTH response and could be responsible for the citrate toxicity symptoms observed during apheresis. We investigated the time course of changes in the concentrations of ionized Mg (iMg) and ionized Ca (iCa), and other electrolytes, which occur during large-volume leukapheresis (LVL) procedures in healthy donors, and their relation to the citrate toxicity symptoms. During the LVL procedure (duration from 2.5 to 6 hours, with and without Ca supplementation [IV Ca chloride, Ca gluconate]), the concentration of citrate increased and iCa, iMg, K, and Pi concentrations decreased. The maximum extent to which these analytes changed was as follows (mean; range): citrate (3.96 mmol/L; 1.14 to 8.64 mmol/L), iCa (-0.29 mmol/L; -0.06 to -0.47 mmol/L), iMg (-0.19 mmol/L; -0.07 to -0.28 mmol/L), potassium (-0.6 mmol/L; -1.2 to 0.1 mmol/L), inorganic phosphate (-0.27 mmol/L; -0.77 to 0.03 mmol/L). The time at which the maximum changes occurred was different for each LVL procedure. Highly significant correlations (p less than 0.0001) occurred between citrate and total and ionized Ca and Mg, inorganic phosphorus, and potassium. The concentration of intact PTH increased within the first 30 minutes of citrate infusion and then gradually declined during the LVL procedure. The maximum extent of the increase was mean, 105 ng/L; range, 9?258 ng/L. This study shows that, in addition to the physiologically important changes in serum iCa, the concentrations of iMg and potassium are also significantly affected by the citrate. We are investigating the effect of oral calcium supplementation on acute electrolyte changes during LVL procedures.